Skip to main content

The beneficial effects of inhaled nitric oxide in patients with severe traumatic brain injury complicated by acute respiratory distress syndrome: a hypothesis

Abstract

Background

The Iraq war has vividly brought the problem of traumatic brain injury to the foreground. The costs of death and morbidity in lost wages, lost taxes, and rehabilitative costs, let alone the emotional costs, are enormous. Military personnel with traumatic brain injury and acute respiratory distress syndrome may represent a substantial problem. Each of these entities, in and of itself, may cause a massive inflammatory response. Both presenting in one patient can precipitate an overwhelming physiological scenario. Inhaled nitric oxide has recently been demonstrated to have anti-inflammatory effects beyond the pulmonary system, in addition to its ability to improve arterial oxygenation. Furthermore, it is virtually without side effects, and can easily be applied to combat casualties or to civilian casualties.

Presentation of hypothesis

Use of inhaled nitric oxide in patients with severe traumatic brain injury and acute respiratory distress syndrome will show a benefit through improved physiological parameters, a decrease in biochemical markers of inflammation and brain injury, thus leading to better outcomes.

Testing of hypothesis

A prospective, randomized, non-blinded clinical trial may be performed in which patients meeting the case definition could be entered into the study. The hypothesis may be confirmed by: (1) demonstrating an improvement in physiologic parameters, intracranial pressure, and brain oxygenation with inhaled nitric oxide use in severely head injured patients, and (2) demonstrating a decrease in biochemical serum markers in such patients; specifically, glial fibrillary acidic protein, inflammatory cytokines, and biomarkers of the hypothalamic-pituitary-adrenal axis, and (3) documentation of outcomes.

Implications of hypothesis

Inhaled nitric oxide therapy in traumatic brain injury patients with acute respiratory distress syndrome could result in increased numbers of lives saved, decreased patient morbidity, decreased hospital costs, decreased insurance carrier and government rehabilitation costs, increased tax revenue secondary to occupational rehabilitation, and families could still have their loved ones among them.

Peer Review reports

Background

Traumatic brain injury (TBI) affects 1.4 million Americans annually, which includes 1.1 million emergency department visits, 235,000 hospitalizations, and 50,000 deaths [1]. Approximately 5.3 million Americans are disabled with TBI [2] at a cost of $60 billion annually [3]. The Iraq war has provided additional cases and cost. At least 28% of wounded personnel have TBI resulting in $600,000 to $4,300,000 of care per patient [46]. This is based on 2824 wounded personnel as of August 2005 [6].

Complications occur frequently in TBI, and respiratory dysfunction represents a primary non-neurological system failure [7]. These patients are confronted with a massive inflammatory response with the release of cytokines [8] and neuropeptides [9] that are deleterious to the brain. Furthermore, this inflammatory response renders the lungs less tolerant of stressors causing ischemia-reperfusion and subsequent mechanical insults [10], i.e., massive brain injury may incite ventilator induced lung injury. This occurs through neurogenic pulmonary edema [7], ventilator associated pneumonia [11], and/or acute lung injury (ALI)/adult respiratory distress syndrome (ARDS) [12] that may be secondary to inflammatory ultrastructural changes in pneumatocyte type II cells [13] through the initiation/migration of activated neutrophils into the lungs [14]. In the face of severe pulmonary insufficiency, such as occurs in neurogenic pulmonary edema, pneumonia, and ALI/ARDS, oxygen delivery to the brain may be compromised. INO delivered at 10–80 parts per million is an effective pulmonary vasodilator that rapidly degrades in vivo [15] and improves arterial oxygenation [1620]. However, clinical trials have not shown improved outcomes with its use in ARDS [2123], including a large phase III study in the United States [24]. Nonetheless, inhaled nitric oxide (INO) has been successfully used twice in TBI patients with ALI/ARDS [25, 26].

In severe TBI (Glasgow coma scale {GCS} ≥ 8) it has been recommended that the partial pressure of oxygen in arterial blood be maintained at a minimum of 100 mm Hg [27], cerebral perfusion pressure maintained between 60–70 mm Hg [28], and the partial pressure of carbon dioxide in arterial blood maintained at 32–35 mm Hg [29]. Increased intracranial pressure (ICP) may then be prevented from occurring. Effective oxygen delivery and decreased inflammation will assist in meeting these parameters.

Very recent basic science and clinical research has brought into question the results of the above-mentioned ARDS trials, especially as they may relate to TBI. Mathru et al have demonstrated that INO attenuates ischemia-reperfusion injury in the lower extremities of humans [30], and Gazoni et al have demonstrated such attenuation in animal lungs [31]. Hu et al concluded that INO decreased oxidative damage and inflammation along with reduced alveolar leakage in mature adult rat lungs [32]. Most importantly, Aaltoren et al have shown that pigs with meconium aspiration have hippocampal neuronal injury [33], however when INO is administered to pigs with meconium aspiration, hippocampal neuronal injury is inhibited [34]. This occurs through diminished DNA oxidation in the hippocampus and is accompanied by decreased levels of glutathione, a biomarker of oxidative stress [34]. Finally, Da et al demonstrated that INO, with concurrent administration of steroids, will decrease the inflammatory response in porcine sepsis through up-regulation of the glucocorticoid receptor (GR) [35].

Thus, use of INO in patients with severe TBI and ARDS will show a benefit through improved physiological parameters and a decrease in biochemical markers of inflammation and brain injury, leading to better outcomes.

Presentation of the hypothesis

While INO is a potent pulmonary vasodilator, and has been thought to remain only in the pulmonary system, recent work has demonstrated that INO may go downstream to improve other organs [35] in the following manner. The view that red blood cells (RBC) consume NO has been altered to one in which the RBC is a deliverer of NO [36]. NO reacts, not only with heme iron, but also with cysteine (Cys)-93 on the hemoglobin β-unit [37]. NO reactions with heme iron cause NO's inactivation, but S-nitrosylation of Cys-93 makes hemoglobin a carrier of NO bioactivity [38]. Also, an increase in S-nitrosothiol proteins occurs in sepsis (including RBC S-nitrosothio-hemoglobin and hemoglobin [Fe]NO) [39, 40]. This accumulation of hemoglobin [Fe]NO as a 5-coordinate α-heme NO does not allow NO release to the Cys-β93 residue. However, dissociation of oxygen from the 5-coordinate α-heme-NO occurs so that delivery of oxygen occurs without an extensive vasodilation [41]. Thus, according to Goldfarb and Cinel, NO excess that interacts with hemoglobin will lead to products that prevent NO toxicity [42]. Goldfarb and Cinel also point out that S-nitrosylated albumin can transport NO bioactivity downstream, i.e., to other organs [42] and that NO stabilized through hemoglobin or other proteins by reversible S-nitrosylation may be the way NO extrapulmonary effects get downstream [42].

INO and glucocorticoid regulation may be important, not only in sepsis, but also in TBI. Da et al have demonstrated that glucocorticoid receptor (GR) up-regulation decreased the inflammatory response in a porcine model of sepsis using INO in combination with glucocorticoids (neither intervention worked well alone) [35]. In contrast to Da's work, though, up-regulation of GR in the central nervous system has been considered detrimental in some animal models of TBI [4346], but these studies did not involve INO. In humans high levels of total serum cortisol (CORT), adrenocorticotropic hormone (ACTH), and catecholamines are present early in TBI [47, 48]. However, a low plasma ACTH concentration early in TBI is associated with better intensive care unit survival [49, 50]. This may be part of an adaptive down-regulation as demonstrated by Lee et al in which cortical GR expression was down regulated after 6 hours of injury in the ischemic cortex of rats [51]. Thus indicating an organism's attempt at neuroprotection. It may be that INO reaching the central nervous system allows brain GR to be down regulated.

In view of new findings on its downstream effects and lack of side effects [52], INO may be delivered to the brain and cause GR expression in the brain/hippocampus to be muted. Thus enhancing a neuroprotective effect while at the same time allowing the rest of the body to up-regulate GR in response to steroids and INO administration, and assisting the body in its anti-inflammatory efforts.

Testing the hypothesis

The hypothesis may be confirmed by achieving the following aims: (1) demonstrating an improvement in physiologic parameters, ICP, and brain oxygenation with INO use in patients with severe TBI, and (2) demonstrating a decrease in biochemical serum markers of TBI with INO use. Specifically, glial fibrillary acidic protein (GFAP, which is specific for TBI [53, 54]), inflammatory cytokines (TGF-β, TNF-α, IL-2, IL-6, IL-1β), CORT, ACTH, and cortisol-binding globulin will be evaluated.

A prospective, randomized, non-blinded clinical trial may be performed in which patients meeting the following case definition could be entered into the study: a subject whose GCS is ≥ 8, who has clinically qualified for intracranial pressure monitoring, whose trachea is intubated, whose oxygenation and ventilation is being supported by a ventilator, and in whom the ratio of partial pressure of oxygen in arterial blood to inspired oxygen is less than 200 with radiographic evidence of lung injury. The subjects should be randomized into two groups, those that will receive treatment without INO, and those who will receive INO. Invasive monitoring of CNS, renal, and cardiopulmonary parameters will be necessary. Follow-up at 28 days and 6 months can be through hospital records, an information-gathering tool, and the social security death index.

Biochemical markers will be evaluated by enzyme-linked immunosorbent assays (ELISA). Physiologic monitors shall include: pulmonary artery catheter for cardio-pulmonary-vascular indices (cardiac output (CO), cardiac index (CI), mixed venous oxygenation (SVO2), central venous pressure (CVP), systemic vascular resistance index (SVRI), pulmonary vascular resistance index (PVRI), stroke volume index (SVI), right ventricular ejection fraction (RVEF), right ventricular end diastolic volume (RVEDV), left ventricular stroke work index (LVSWI), right ventricular stroke work index (RVSWI), oxygen delivery (DO2), oxygen uptake (VO2), and oxygen extraction ratio (O2ER)), arterial line for blood pressure, foley catheter with abdominal pressure monitor, LICOX® Brain Oxygen tissue monitor (records brain partial pressure of oxygen, intracranial pressure, and brain temperature), cerebral oximetry, pulse oximetry, and transcranial doppler monitor for middle cerebral artery velocities. Also arterial blood gases, cerebral perfusion pressure, lactate, and methemoglobin will be monitored.

The subjects' entire physiologic/biochemical/hematologic profiles will be available for analysis, such as hemoglobin, hematocrit, electrolytes, etc., as will the injury severity score (ISS) and Apache II score.

Implications of hypothesis

Inhaled nitric oxide in humans with TBI and ARDS has been used successfully on two occasions to improve outcomes. It has also been shown to be effective in hippocampal preservation in animals. Positive results could immediately affect treatment of military and civilian TBI patients worldwide. A decreased inflammatory response and increased arterial oxygen tension in TBI patients with ARDS, through the use of INO, could potentially lead to decreased ICP and better brain oxygenation. This would result in increased numbers of lives saved, decreased patient morbidity, decreased hospital costs, decreased insurance carrier and government rehabilitation costs, increased tax revenue secondary to occupational rehabilitation, and families could stay intact.

References

  1. 1.

    Murray CJ, Lopes AD, (eds): Global Health Statistics; Geneva. 1996, World Health Organization

    Google Scholar 

  2. 2.

    Thurman D, Alverson C, Dunn K, Guerrero J, Sniezek J: Traumatic brain injury in the United States: a public health perspective. J Head Trauma Rehabil. 1999, 14: 602-615.

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Finkelstein E, Corso P, Miller T: The incidence and economic burden of injuries in the United States. 2006, New York: Oxford University Press

    Google Scholar 

  4. 4.

    Warden D: Military TBI during the Iraq and Afghanistan Wars. J Head Trauma Rehabil. 2006, 21: 398-402.

    Article  PubMed  Google Scholar 

  5. 5.

    The economic costs of the Iraq war.http://www.informationclearinghouse.info/article11495.htm

  6. 6.

    Wallsten S, Korsec K: The economic cost of the war in Iraq. The Brookings Institute Working Paper 2005. 2005, 5-19.

    Google Scholar 

  7. 7.

    Zygun DA, Kortbeek JB, Fick GH, Laupland KB, Doig CJ: Non-neurologic organ dysfunction in severe traumatic brain injury. Crit Care Med. 2005, 33: 654-660. 10.1097/01.CCM.0000155911.01844.54.

    Article  PubMed  Google Scholar 

  8. 8.

    Moranti-Kossman MC, Rancan M, Stahel PF, Kossman T: Inflammatory response in acute brain injury: a double-edged sword. Curr Opin Crit Care. 2002, 8: 101-105. 10.1097/00075198-200204000-00002.

    Article  Google Scholar 

  9. 9.

    Rall JM, Matslievich DA, Dash PK: Comparative analysis of mRNA levels in the frontal cortex and the hippocampus in the basal state and in response to experimental brain injury. Neuropathol Appl Neurobiol. 2003, 29: 18-131. 10.1046/j.1365-2990.2003.00439.x.

    Article  Google Scholar 

  10. 10.

    Lopes-Aguilar J, Villagra Ana, Bernabe F, Murias G, Piacentini E, Real J, Fernandez-Segoviano P, Romero PV, Hotchkiss JR, Blanch L: Massive brain injury enhances lung damage in an isolated lung model of ventilator-induced injury. Crit Care Med. 2005, 33: 1077-1083. 10.1097/01.CCM.0000162913.72479.F7.

    Article  Google Scholar 

  11. 11.

    Zygun DA, Zuege DJ, Boiteau PJ, Laupland KB, Henderson EA, Kortbeek , Doig CJ: Ventilator-associated pneumonia in severe traumatic brain injury. Neurocrit Care. 2006, 5: 108-114. 10.1385/NCC:5:2:108.

    Article  PubMed  Google Scholar 

  12. 12.

    Holland MC, Mackersie RC, Morabito D, Campbell AR, Kivett VA, Patel R, Erickson VR, Pittet JF: The development of acute lung injury is associated with worse neurologic outcome in patients with severe traumatic brain injury. J Trauma. 2003, 55: 106-111.

    Article  PubMed  Google Scholar 

  13. 13.

    Yildirim E, Katanoglu E, ozsisik K, Beskonakli E, Ozer S, Mustafa F, Kamer K, Unal S: Ultrastructural changes in pneumatocyte type II cells following traumatic brain injury in rats. Eur J Cardiothorac Surg. 2004, 25: 523-529. 10.1016/j.ejcts.2003.12.021.

    Article  PubMed  Google Scholar 

  14. 14.

    Strieter RM, Kunkel SL: Acute Lung Injury: the role of cytokines in the elicitation of neutrophils. J Investig Med. 1994, 42: 640-651.

    CAS  PubMed  Google Scholar 

  15. 15.

    Griffiths MJD, Evans TW: Inhaled nitric oxide therapy in the adult. N Eng J Med. 2005, 353: 2683-2695. 10.1056/NEJMra051884.

    CAS  Article  Google Scholar 

  16. 16.

    Herridge MS, Cheung AM, Tansy CM, Matte-Martyn A, Diaz-Granados N, Al-Saidi F, Cooper AB, Guest CB, Mazer CD, Mehta S, Stewart TE, Barr A, Cook D, Slutsky AS, Arthur S: One-year outcomes in survivors of acute respiratory distress syndrome. N Eng J Med. 2003, 348: 683-693. 10.1056/NEJMoa022450.

    Article  Google Scholar 

  17. 17.

    Rubenfeld GD, Caldwell E, Peabody E, Weaver J, Martin DP, Neff M, Stern EJ, Hudson LD: Incidence and outcomes of acute lung injury. N Eng J Med. 2005, 353: 1685-1693. 10.1056/NEJMoa050333.

    CAS  Article  Google Scholar 

  18. 18.

    Herridge MS, Angus DC: Acute Lung Injury – affecting many lives. N Eng J Med. 2005, 353: 1736-1738. 10.1056/NEJMe058205.

    CAS  Article  Google Scholar 

  19. 19.

    Bennet D, (ed): Proceedings of the 9th European Congress in Intensive Care Medicine: 1996; Bologna. Moduzzi Editore. 1996

    Google Scholar 

  20. 20.

    Abman SH, Greibel JL, Parker DK, Schmidt JM, Swanton D, Kinsella JP: Acute effects of inhaled nitric oxide in children with severe hypoxemic respiratory failure. J Pediatr. 1994, 124: 881-888. 10.1016/S0022-3476(05)83175-0.

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Dellinger RP, Zimmerman JL, Taylor RW, Straube RC, Hauser DL, Criner GJ, Davis K, Hyers TM, Papadakos P: Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome: results of a randomized phase II trial. Inhaled Nitric Oxide in ARDS Study Group. Crit Care Med. 1998, 26: 15-23. 10.1097/00003246-199801000-00011.

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Lundin S, Mang H, Smithies M, Stenqvist O, Frostell C: Inhalation of nitric oxide in acute lung injury: results of a European mulitcentre study. Intensive Care Med. 1999, 25: 911-919. 10.1007/s001340050982.

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Rossaint R, Gerlach H, Schmidt-Ruhnke H, Pappert D, Lewandowski K, Steudel W, Falke K: Efficacy of inhaled nitric oxide in patients with severe ARDS. Chest. 1995, 107: 1107-1115. 10.1378/chest.107.4.1107.

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Angus DC, Clermont G, Linde-Zwirble WT, Musthafa AA, Dremsizov TT, Lidicker J, Lave JR: Healthcare costs and long-term outcomes after acute respiratory distress syndrome: a phase III trial of inhaled nitric oxide. Crit Care Med. 2006, 34: 2883-2890.

    Article  PubMed  Google Scholar 

  25. 25.

    Peillon D, Jault V, Le Vavaseur O, Bellanger-Depagne JJ, Combe C: Effect du monoxyde d'azote inhale chez une patiente atteinte d'hypertension intracranienne. Ann Fr Anesth Reanim. 1999, 18: 225-229. 10.1016/S0750-7658(99)80073-2.

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Vavilala MS, Roberts JS, Moore AE, Newell DW, Lam AM: The influence of inhaled nitric oxide on cerebral blood flow and metabolism in a child with traumatic brain injury. Anesth Analg. 2001, 93: 351-353. 10.1097/00000539-200108000-00023.

    CAS  PubMed  Google Scholar 

  27. 27.

    Cohen SM, Marion DW: Traumatic Brain Injury. Textbook of Critical Care. Edited by: Fink MP, Abraham E, Vincent J-L, Kochanek PM. 2005, Philadelphia: Elsevier, 377-385. 5

    Google Scholar 

  28. 28.

    Rosner MJ, Rosner SD: Cerebral perfusion in head injury. Intracranial Pressure VIII. Edited by: Avezaat CJJ, van Eijndhoven JHM, Maas AIR. 1993, Berlin: Springer-Verlag, 540-545.

    Google Scholar 

  29. 29.

    Stocchetti N, Maas AIR, Chieregato A, van der Plas AA: Hyperventilation in head injury: a review. Chest. 2005, 127: 1812-1827. 10.1378/chest.127.5.1812.

    Article  PubMed  Google Scholar 

  30. 30.

    Mathru M, Huda R, Solanki DR, Hays S, Lang JD: Inhaled nitric oxide attenuates reperfusion inflammatory responses in Humans. Anesthesiology. 2007, 106: 275-282. 10.1097/00000542-200702000-00015.

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    Gazoni LM, Tribble CG, Zhao MQ, Unger EB, Farrar RA, Ellman PI, Fernandez LG, Laubach VE, Kron IL: Pulmonary macrophage inhibition and inhaled nitric oxide attenuate lung ischemia-reperfusion injury. Ann Thorac Surg. 2007, 84: 247-253. 10.1016/j.athoracsur.2007.02.036.

    Article  PubMed  Google Scholar 

  32. 32.

    Hu X, Guo C, Sun B: Inhaled nitric oxide attenuates hyperoxic and inflammatory injury without alteration of phosphatidylcholine synthesis in rat lungs. Pulm Pharmacol Ther. 2007, 20: 75-84. 10.1016/j.pupt.2005.12.008.

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Aaltonen M, Soukka H, Halkila L, Kalimo H, Holopainen IE, Kaapa PO: Meconium aspiration induces neuronal injury in piglets. Acta Paediatr. 2005, 94: 1468-1475. 10.1080/08035250510042816.

    Article  PubMed  Google Scholar 

  34. 34.

    Aaltonen M, Soukka H, Halkola L, Jalonen J, Kalimo H, Holopainen IE, Kaapa PO: Inhaled nitric oxide treatment inhibits neuronal injury after meconium aspiration in piglets. Early Hum Dev. 2007, 83: 77-85. 10.1016/j.earlhumdev.2006.05.003.

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Da J, Chen L, Hedenstierna G: Nitric oxide up-regulates the glucocorticoid receptor and blunts the inflammatory reaction in porcine endotoxin sepsis. Crit Care Med. 2006, 35: 26-32. 10.1097/01.CCM.0000250319.91575.BB.

    Article  Google Scholar 

  36. 36.

    Gow AJ: The biological chemistry of nitric oxide as it pertains to the extrapulmonary effects of inhaled nitric oxide. Proc Am Thorac Soc. 2006, 3: 150-152. 10.1513/pats.200506-058BG.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Luchsinger BP, Rich EN, Gow AJ, Williams EM, Stamler JS, Singel DJ: Routes to S-nitroso-hemoglobin formation with heme redox and preferential reactivity in the B subunits. Proc Nat Acad Sci USA. 2003, 100: 461-466. 10.1073/pnas.0233287100.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Robinson JM, Lancaster JR: Hemoglobin-mediated, hypoxia-induced vasodilation via nitric oxide: mechanism(s) and physiologic versus pathological relevance. Am J Respir Cell Mol Biol. 2005, 32: 257-261. 10.1165/rcmb.F292.

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Kosaka H, Watanabe M, Yoshihara H, Shiga T: Detection of nitric oxide production in lipopolysaccharide-treated rats by ESR using carbon monoxide hemoglobin. Biochem Biophys Res Commun. 1992, 184: 1119-1124. 10.1016/0006-291X(92)90708-S.

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    Jourd'heuil D, Gray L, Grisham MB: S-nitrosothiol formation in blood of lipopolysaccharide-treated rats. Biochem Biophys Res Commun. 2000, 273: 22-26. 10.1006/bbrc.2000.2892.

    Article  PubMed  Google Scholar 

  41. 41.

    Doctor A, Platt R, Sheram ML, Eisheid A, McMahon T, Doherty J, Axelrod M, Kline J, Gurka M, Gow A, Gaston B: Hemoglobin confirmation couples erythrocyte S-nitrosothiol content to O2 gradients. Proc Nat Acad Sci USA. 2005, 102: 5709-5714. 10.1073/pnas.0407490102.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Goldfarb RD, Cinel I: Inhaled nitric oxide therapy for sepsis: more than just lung. Crit Care Med. 2007, 35: 290-291. 10.1097/01.CCM.0000251290.41866.2B.

    Article  PubMed  Google Scholar 

  43. 43.

    McCullers DL, Herman JP: Adrenocorticosteroid receptor blockade and excitotoxic challenge regulated adrenocorticosteroid receptor mRNA levels in the hippocampus. J Neurosci Res. 2001, 64: 277-283. 10.1002/jnr.1076.

    CAS  Article  PubMed  Google Scholar 

  44. 44.

    McCullers DL, Sullivan PG, Scheff SW, Herman JP: Traumatic brain injury regulates adrenocorticosteroid receptor mRNA levels in rat hippocampus. Brain Res. 2002, 947: 41-49. 10.1016/S0006-8993(02)02904-9.

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    McCullers DL, Sullivan PG, Scheff SW, Herman JP: Mifepristone protects CA1 hippocampal neurons following traumatic brain injury in rat. Neuroscience. 2002, 109: 219-230. 10.1016/S0306-4522(01)00477-8.

    CAS  Article  PubMed  Google Scholar 

  46. 46.

    Herman JP, Seroogy K: Hypothalamic-pituitary-adrenal axis, glucocorticoids, and neurologic disease. Neurol Clin. 2006, 24: 461-481. 10.1016/j.ncl.2006.03.006.

    Article  PubMed  Google Scholar 

  47. 47.

    Bondanelli M, Ambrosio M, Zatelli MC, De Marinis L, Delgi U, Ettore C: Hypopituitarism after traumatic brain injury. Eur J Endocrinol. 2005, 152: 679-691. 10.1530/eje.1.01895.

    CAS  Article  PubMed  Google Scholar 

  48. 48.

    Van den Berge G: Novel insights into the neuroendocrinology of critical illness. Eur J Endocrinol. 2000, 143: 1-13. 10.1530/eje.0.1430001.

    Article  Google Scholar 

  49. 49.

    Llompart-Pou JA, Raurich JM, Ibanez J, Burguera B, Barcelo A, Ayestaran JI, Prerezx-Barcena J: Relationship between plasma adrenocorticotropin hormone and intensive care unit survival in early traumatic brain injury. J Trauma. 2007, 62: 1457-1461.

    CAS  Article  PubMed  Google Scholar 

  50. 50.

    Koiv L, Merisalu E, Zilmer K, Tomberg T, Kaasik AE: Changes of sympatho-adrenal and hypothalamo-pituitary-adrenocortical system in patients with head injury. Acta Neurol Scand. 1997, 96: 52-58.

    CAS  Article  PubMed  Google Scholar 

  51. 51.

    Lee BH, Wen TC, Rogido M, Sola A: Glucocorticoid receptor expression in the cortex of the neonatal rat brain with and without focal ischemia. Neonatology. 2007, 91: 12-19. 10.1159/000096966.

    CAS  Article  PubMed  Google Scholar 

  52. 52.

    Sokol J, Jacobs SE, Bohn D: Inhaled nitric oxide for acute hypoxemic respiratory failure in children and adults. Cochrane Database Syst Rev. 2003, CD002787-10.1002/14651858. , 1

  53. 53.

    Pelinka LE, Kroepfl A, Leixnering M, Buchinger W, Raabe A, Redl H: GFAP versus S100B in serum after traumatic brain injury: relationship to brain damage and outcome. J Neurotrauma. 2004, 21: 1553-1561. 10.1089/neu.2004.21.1553.

    Article  PubMed  Google Scholar 

  54. 54.

    Pelinka LE, Kroepfl A, Schmidhammer R, Krenn M, Buchinger W, Redl H, Raabe A: Glial fibrillary acidic protein in serum after traumatic brain injury and multiple trauma. J Trauma. 2004, 57: 1006-1012.

    CAS  Article  PubMed  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Thomas J Papadimos.

Additional information

Competing interests

The author(s) declare that they have no competing interests.

Rights and permissions

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Reprints and Permissions

About this article

Cite this article

Papadimos, T.J. The beneficial effects of inhaled nitric oxide in patients with severe traumatic brain injury complicated by acute respiratory distress syndrome: a hypothesis. J Trauma Manage Outcomes 2, 1 (2008). https://doi.org/10.1186/1752-2897-2-1

Download citation

Keywords

  • Traumatic Brain Injury
  • Glucocorticoid Receptor
  • Acute Respiratory Distress Syndrome
  • Cerebral Perfusion Pressure
  • Severe Traumatic Brain Injury